Use of ganciclovir in the treatment of acquired cytomegalovirus disease in a preterm infant

The first use of ganciclovir in a preterm infant is reported. The 27 week appropriate-for-gestational-age male infant developed a disseminated cytomegalovirus infection subsequent to a blood transfusion. A daily dose of 10 mg/kg administered intravenously in two divided doses for a total of 14 days was given without adverse clinical or toxic effects. The patient has remained well following discharge from hospital.

d rug gan ciclovir (9-11.3-dihyroxy-2-propoxymelhyl] guanine.DHPG) is effective in the treatm ent of serious CMV infections in immunocompromised h osts (6)(7)(8).The s uccessful u se of gan ciclovir is reported in a pre term infant who developed a disseminated CMV infection s u bsequent to blood transfusion.This is the firs t reported use of gan ciclovir in a neonate.

CASE REPORT
A 27 week appropriate-for-gestation a l-age male infan t weighing 1010 g was born by s pontaneou s vagina l de livery lo a 23-year -old mother.Apgar scores were six a t I min and seven a t 5 mins.Th e n eonate developed hyaline membrane disease and required assisted ventilation for 15 days and supplemental o>.ygen for a further 24 days.Subsequent progress was com plicated by the development of bronchopulmonary dysplasia and retinopathy of prematu rity.From day 46 onward.the patien t became increasingly lethargic and developed an increasing number of apneic allacks with bradycardias and a n increasing oxygen requirement.He was s u bseq u ently found to be hypotonic with marked hepatosplenomegaly.Following a full work-up for sepsis the patient was started on a course of b road spectrum antibiotics: however. he continued to deteriorate.and by day 56 required reintubation and assisted ventilation.Generalized petechiae over the skin, and recurrence of jaundice with mild direct (conjugated) hyperbilirubinemia.proteinuria and hematuria were noted.His platelet count was 59 x 10 9 /Lwilh a hematocrit of0.42 L/L (42%).reticulocyte count of 126 x 10 9 /L (3.8/ 100 RBC) and fibrin degradation products 40 to 80 mg/L.Direct and indirect Coombs' tests were n egative.Blood, cerebrospinal Ouid and urine cultures were negative and the antibiotics were slopped after 48 h.During these first eight weeks of life.the patient had received six transfusions of packed red blood cells from different donors to replace blood lost. in order to maintain a hematocrit greater than 0.40 L/L (40o/o).
Ophthalmological assessment on day 60 revealed the presence of chorioretinitis.Urine samples taken on days 55 and 60 demonstrated a positive cytopathic effect from CMV.The presence of CMV in the urine.associated with hepatosplenomegaly, thrombocytopenia.pneumonia.and chorioretinitis.confirmed a clinical diagnosis of d isseminated CMV disease.One transfusion of red b lood cells that the patien t received at day 9 was found in retrospect to be CMV antibody-positive.Normally all blood administered to babies in this unit is prescreened to be CMV antibody-negative.In view of the patient's critical state informed written parental consent was obtained for treatment with ganciclovir.A daily dose of 10 mg/kg administered intravenous ly in two divided doses was started on day 68.Further ophthalmological examination on day 74 revealed stage Ill retinopathy of prematurity.with no chorioretinitis.Ganciclovir was discontinued after a total of 14 days of treatment.There were no adverse clinical or toxic effects while on ganciclovir.The patient was discharged home on day 87 off oxygen.weighin g 2600 g (lOth percentile ) with a length or 46 em (lOth percentile) and a head circumference of33.3 em (40th percentile).His chest was clear to auscultation with the liver palpable 4 em below the right costal margin.and spleen palpable 3 e m below the left costal margin.Examination of the central nervous system was normal.No significant side effects from ganciclovir were observed.other Ganc iclovir fo r CMV in an infant than transien t mild elevation of liver enzymes.Leu kopenia.feeding intolerance.gastrointestinal hemorrhage and hypotension did not occur.No fur•thcr blood transfusions were required.Pre-a nd post treatmen t immunoglobulin levels were norma l.CMV anti body status was negative at the start of ganciclovir treatment.but later he became positive to CMV by both lgG and lgM ELISA.Urine cultures were negative three weeks after the course of ganciclovir and remained negative for CMV at four and six month follow-up examinations.
The patient has remained well following d ischarge from hospital, and follow-up at a chronological age of seven months with an adjusted age of four months showed his weight and length to be on the fifth percentile (weight 5 kg.length 59 em) and h ead circumference on the 40th percentile (41 em).Mild ch est wall retractions with expiratory rhonchi on auscultation were fell to be compatible with the sequelae of bronchopu lmonary dysplasia.His abdomen was protuberant with the liver palpable 1 em below the right costal margin.There was no splenomegaly.The only abnonnalilies on neurological exam were bilateral exaggeration of his popliteal angles to between 120° and 150° with bilaterally exaggerated knee jerks and inconstant clonus of the left ankle.His gross motor function was at a four to five month level and fine motor function at a three month level.Ophthalmological exam showed no evidence of chorioretinitis.Auditory brain response testing confirmed that hearing in both ears was normal.

DISCUSSION
This patient developed symptomatic CMV infection \vith hepatosplenomegaly.thrombocytopenia.petechiae.jaundice with mild di rect (conjugated) hyperbilirubinemia.pneumonia and chorioretin itis following a CMV antibody-positive transfusion.After 14 days of ga.nciclovir, no persistence of CMV infection was found.During therapy.no significant side effects other than transiently elevated liver function tests were observed.As this patient is at high risk for developmental.sensory.cognitive and intellectual deficits (5.9.1 0).further long term fo llow-up will determine whether treatment with ganciclovir has altered or modified the patient's h igh risk category.The good clinical response and rapid improvement in ophthalmological findings are encouraging.and suggest that further clinical studies using ganciclovir to treat acquired CMV disease need to be undertaken to determine its phannacokinetics.efficacy and benefit in lhe neonatal and immediate post natal period.